Project Summary Pancreatic Ductal Adenocarcinoma (PDAC) has a dismal prognosis with a median survival of about 6 months for patients with metastatic disease despite the use of current treatments. Therefore, PDAC is in urgent need of effective therapies. About 80% of PDAC patients exhibit mutation in KRAS, with substitution of a glycine residue at codon 12, such as KRASG12D, observed in high frequency. Many studies in mice unequivocally show that direct inhibition oncogenic KRAS significantly suppresses tumor progression. Despite such compelling evidence for the functional role of oncogenic KRAS in the PDAC pathogenesis, direct targeting of oncogenic KRAS has been elusive and it has often been dubbed as ?undruggable?. In this grant application, we propose to explore a novel approach to target oncogenic KRAS using physiological nanoparticles known as exosomes. Exosomes are 40-150 nm extracellular vesicles (EVs) that contain DNA, RNA and proteins, and can deliver their contents efficiently into cells they fuse with and/or enter. Exploiting this unique feature of exosomes, our research team proposes in this grant application to test the central hypothesis that ?exosomes can be engineered to deliver RNA interference (RNAi) molecules to target KRASG12D in pancreatic cancer?. Successful completion of the proposed studies will determine whether exosomes exhibit a superior ability to deliver RNAi molecules for the treatment of pancreatic cancer when compared to liposomes. Additionally, after such increased ability is investigated using multiple experimental systems, the proposal will further identify mechanism/s associated with the enhanced efficacy of exosomes in the delivery of RNAi molecules. Collectively, the proposal is designed to enable in-depth pre-clinical studies coupled with an investigation into the unique mechanism of action of exosomes to potentially facilitate future therapeutic testing in patients with PDAC.